JNK is among the mitogen activated protein kinases (MAPKs) mediating the signaling pathway for intranuclear transmission of extracellular stimuli. It is known that JNK increases the transcription activity by phosphorylation of the N-terminal of c-Jun, which is an AP-1 transcription factor (S. Gupta, T. Barrett, A. J. Whitmarsh, J. Cavanagh, H. K. Sluss, B. Derijard, and R. J. Davis, EMBO J., 15, 2760–2770 (1996), A. Minden, and M. Karin, Biochemica et Biophysica Acta, 1333, F85 (1997)). In other words, it is considered that JNK inhibitors inhibit expression of AP-1-dependent inflammatory and immune-factors, and are potential therapeutic drugs of inflammatory diseases such as rheumatoid arthritis and the like, and neurodegenerative diseases (J. L. Swantek, M. H. Cobb, and T. D. Geppert, Mol. Cell. Biol., 1997, 17, 6274, A. C. Maroney, M. A. Glicksman, A. N. Basma, K. M. Walton, E. Knight Jr, C. A. Murphy, B. A. Bartlett, J. P. Finn, T. Angeles, Y. Matsuda, N. T. Neff, and C. A. Dionne, J. Neurosci., 1998, 18, 104).
Involvement of c-Jun in myocardial apoptosis during ischemia/reperfusion has been also suggested, thereby indicating a potential of JNK for a therapeutic drug of cardiovascular diseases such as cardiac infarction, cardiac incompetence and the like (T.-L. Yue, X.-L. Ma, X. Wang, A. M. Romanic, G.-l. Liu, C. Louden, J.-L. Gu, S. Kumar, G. Poste, R. R. Ruffolo Jr, and G. Z. Feuerstein, Circ. Res., 82, 166(1998)).
As having such JNK inhibitory activity, oxyindole derivatives are described in WO00/64872 and uracyl derivatives are described in WO00/75118.
On the other hand, as pyridyl-azole compounds and pyrimidinyl-azole compounds, the following compounds are known.
As imidazole compounds, Japanese Patent Application under PCT laid-open under kohyo No. 7-50317 (WO93/14081) describes compounds having cytokine inhibitory activity. As oxazole derivatives, Japanese Patent Application under PCT laid-open under kohyo No. 9-505055 (WO 95/13067) describes compounds having cytokine inhibitory activity. As pyrrole derivatives, Japanese Patent Application under PCT laid-open under kohyo No. 11-510511 (WO 97/05878) describes compounds having cytokine inhibitory activity and glucagon-antagonistic activity.
As thiazole compounds, moreover, the following compounds and the like are known:    1) 1,3-thiazole derivatives represented by the formula:
wherein R1 represents a cycloalkyl group, a cyclic amino group, an amino group optionally having, as substituent(s), 1 or 2 lower alkyl, phenyl, acetyl or lower alkoxycarbonylacetyl, an alkyl group optionally having, as substituent(s), hydroxyl, carboxyl or lower alkoxycarbonyl, or a phenyl group optionally having, as substituent(s), carboxyl, 2-carboxyethenyl or 2-carboxy-1-propenyl, R2 represents a pyridyl group optionally having, as substituent(s), lower alkyl, R3 represents a phenyl group optionally having, as substituent(s), lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy, or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, thromboxane A2 (TXA2) synthase-inhibitory, and platelet coagulation-inhibitory activities (JP-A 60-58981),    2) 1,3-thiazole derivatives represented by the formula:
wherein R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino group optionally having substituent(s), R2 represents a pyridyl group optionally substituted with alkyl group(s), R3 represents a phenyl group optionally having substituent(s), or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXA2 synthase-inhibitory, and platelet coagulation-inhibitory activities (JP-A 61-10580),    3) 1,3-thiazole derivatives represented by the formula:
wherein R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino group optionally having substituent(s), R2 represents a pyridyl group optionally substituted with alkyl group(s), R3 represents an aryl group optionally having substituent(s), or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXA2 synthase-inhibitory, and platelet coagulation-inhibitory activities (U.S. Pat. No. 4,612,321),    4) a compound represented by the formula:
wherein R1 represents an optionally substituted phenyl, R2 represents C1-6 alkyl or (CH2)nAr, n represents 0–2, Ar represents an optionally substituted phenyl, R3 represents a hydrogen or C1-4 alkyl, R4 represents a hydrogen, C1-4 alkyl and the like, R5 represents a hydrogen or C1-4 alkyl, R6 represents a hydrogen, C1-4 alkyl and the like, or a salt thereof, having an inhibitory activity of gastric acid secretion (JP-T 7-503023, WO93/15071)    5) a compound represented by the formula:
wherein R1 represents pyridyl and the like, R2 represents phenyl and the like, R3 and R4 represent a hydrogen or methyl, R5 represents methyl and the like, and R6 represents a hydrogen, methyl and the like, or a salt thereof, which is an antiinflammatory agent and antiallergic agent (DE-A-3601411),    6) a compound represented by the formula:
wherein R1 represents a lower alkyl substituted by halogen, R2 represents pyridyl and the like, and R3 represents phenyl and the like, or a salt thereof, having an antiinflammatory, antipyretic, analgesic and antiallergic activity (JP-A-570446), and    7) a thiazole compound represented by the formula:
wherein R represents a lower alkyl group; a lower haloalkyl group; a lower hydroxyalkyl group; a lower alkoxy(lower)alkyl group; an aralkyloxy(lower)alkyl group and the like, R1 represents a cycloalkyl group optionally substituted by lower alkyl group(s) and the like, and R2 represents an optionally substituted aryl group and the like, or a pharmaceutically acceptable salt thereof, having a selective inhibitory activity of TNF-α production and/or IFN-γ production (JP-A-11-49762).    8) as a compound having adenosine A3 receptor antagonistic action, p38 MAP kinase inhibitory action and TNF-α production inhibitory action, an optionally N-oxidized compound represented by the formula:
wherein R1 represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group,    R2 represents an aromatic group optionally having substituents,    R3 represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents,    X represents an oxygen atom or an optionally oxidized sulfur atom,    Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and    Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof, (WO00/64894).    9) a compound represented by the formula:
wherein    R1 is —F, —Cl, —Br, —OH, —SH, —NH2 or —CH3;    R2 is —F, —Cl, —Br, —OH, —SH, —NH2 or —CH3;    R3 is —H, —F, —Cl, —Br, —OH, —SH, —NH2, —CH3, —OCH3 or —CH2CH3;    R4 is —C1-4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl etc.) optionally substituted by a —C3-7 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) (specific examples include propyl, cyclopropylmethyl and the like);    R5 is —C1-4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl etc.) or —C3-7 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) (specific examples include ethyl, cyclopropyl, cyclohexyl and the like), wherein the —C1-4 alkyl is optionally substituted by a phenyl;    D is a bond or an alkyl bridge having 1–3 carbon atoms;    E is —NH— or —NH2+—; and    HETCy is a 4- to 10-membered non-aromatic heterocyclic group containing at least one N atom and optionally containing one or two additional N atoms and 0 or one O or S atom (e.g., pyrrolidinyl, piperidinyl group and the like, particularly preferably 4-piperidinyl group), and optionally substituted by —C1-4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl etc.) or —C(O)—O—CH2 phenyl (specific examples include 4-piperidinyl group, N-methyl-4-piperidinyl group, N-benzyloxycarbonyl-4-piperidinyl group) or a pharmaceutically acceptable salt thereof (WO01/91749).
All the above-mentioned references are quoted in the present specification as references.
As mentioned above, JNK shows various physiological activities by c-Jun phosphorylation, and the development of a JNK inhibitor is desired, which is more satisfactory in terms of effect, prolonged action, safety and the like as a prophylactic or therapeutic drug of various diseases (e.g., rheumatoid arthritis, cardiac ischemia, brain ischemia and the like) due to the excessive activation of c-Jun.